DESCRIPTION: (Applicant's abstract) The immature brain is more susceptible to seizures than the adult brain. This is particularly true for seizures induced by stressful environmental signals such as fever or trauma. Understanding the mechanisms underlying this age-dependent sensitivity is critical for development of treatments for seizures in infants and children. This proposal focuses on the effects of neuroendocrine stress mechanisms on seizure susceptibility in the infant. The applicant has developed models for studying the effects of corticotropin releasing hormone (CRH), a neuroendocrine mediator of stress, on seizure susceptibility in the infant animal. The applicant has shown that CRH promotes infant seizures; conditions which enhance the peptide's activity should augment seizure-induction. Therefore, the tested hypothesis states that cold stress increases CRH-mediated neurotransmission in limbic neurons of the infant rat. This occurs via enhanced CRH synthesis in the amygdala and/or via upregulation of one or both types of CRH receptors in amygdala and hippocampus, and leads to potentiation of limbic seizures, such as those induced by kainate. Four experiments are proposed to test this hypothesis: i) Examination, using the established paradigms of cold stress and limbic seizures, whether cold facilitates kainate seizures in infant rats, and if this is blocked by CRH antagonists. ii) Confirmation and extension of pilot data that CRH facilitates kainate seizures. iii) Determination, using in situ hybridization, whether cold stress increases CRH synthesis and content in the amygdala of the infant rat, and augments synthesis of both novel types of CRH receptors in limbic target neurons. iv) Study of the regulation of CRH gene expression by stress-induced activation of the transcription factor, CREB, using gel-retardation assays and specific immunocytochemistry. This experimental approach is unique in focusing on the interface of environmental stress and epilepsy in the developing brain. The CRH paradigm will enhance the knowledge of the regulation and role of neuropeptides during a critical and little studied period of the developing brain, and may help clarify mechanisms of the enhanced seizure susceptibility at this age. These studies may shed light on mechanisms of human age-specific seizures such as febrile seizures and infantile spasms.